This application relates to chemical compounds which act as agonists of, or otherwise modulate the activity of, GPR131, and to compositions and formulations containing such compounds, and methods of using and making such compounds. The compounds described herein may be used to treat one or more diseases such as diabetes, metabolic syndrome, and liver disease, conditions or symptoms of a disease such as inflammation, and other diseases or conditions for which modulation of GPR131 can provide a therapeutic benefit.
G protein-coupled receptors (GPCRs) comprise a large family of transmembrane receptors that sense molecules outside a cell and modulate signal transduction pathways and, consequently, various cellular responses. GPR131 (also known as BG37, TGR5, M-BAR, GPCR19, MGC40597, GPBAR1, and RUP43) is a GPCR that is activated by bile acids (BAs) such as lithocholic acid (LCA) and taurolithocholic acid (TLC), and oleanolic acid. Muruyama et al., Biochem Biophys Res. Commun., 298:714-9 (2002) [PMID:12419312] (2002); Kawamata et al., J. Biol. Chem., 278:9435-40 (2003) [PMID:12524422]. GPR131 is expressed in the gastro-intestinal tract and adipose as well as other tissues, and is also present in GLP-1 secreting entero-endocrine cell lines such as STC-1 (Katsuma et al., Biochem. Biophys. Res. Commun., 329(1):386-90 (2005) [PMID:15721318]) and NCI-H716. Since this receptor is coupled to signaling through the GαS protein, activation of GPR131 results in increases in cAMP. Bile acid ligands of GPR131 can increase cAMP and consequent release of the incretin hormone glucagon-like-peptide 1 (GLP-1) from enteroendocrine cell lines. Katsuma et al., supra.
GPR131 agonists also increase serum levels of glucagon-like peptide-1 (“GLP-1”) in vivo, and this likely contributes to their ability to improve glucose homeostasis in rodent models. Thomas et al., Cell Metab., 10:167-77 (2009) [PMID:19723493]. Acute improvements in glucose homeostasis due to raising of blood GLP-1 levels by GPR131 agonists may result from increased glucose sensitive insulin secretion (GSIS) from pancreatic beta cells, reduced glucagon secretion from pancreatic alpha cells, and from a delay of gastric emptying, all of which are known effects of GLP-1 in rodents and humans. Drucker, Gastroenterology, 122:531-44 (2002). Multiple current and proposed therapeutic agents for diabetes, obesity and metabolic syndrome have their effect via increased stimulation of the receptor for GLP-1 in pancreatic beta cells or other tissues.
Other consequences of GPR131 activation may also contribute to improvements in glucose homeostasis and other metabolic parameters. GPR131 agonists have been described as having the capacity to increase energy expenditure in rodents, and thus may provide an additional means for improving glucose homeostasis via improvements in insulin sensitivity. Watanabe et al., Nature, 439:484-9 (2006) [PMID:16400329]. In one study, knock-out mice that lacked GPR131 had a higher body weight and increased fat mass relative to wild type mice when placed on a high fat diet suggesting that reduced signaling through GPR131 could contribute to obesity and insulin resistance Muruyama et al., J. Endocrinol., 191:197-205 (2006).
Additionally, GPR131 is expressed in human CD14+ monocytes and spleen, and may play a role in mediating anti-inflammatory effects of BAs and GPR131 agonists. Agonists of this receptor can increase cAMP levels and reduce phagocytic activity in alveolar macrophages. The latter effect may be due to decreased release of pro-inflammatory cytokines in the presence of GPR131 agonists. Kawamata et al, supra. A similar effect has been observed in the resident macrophages of liver (Kupffer cells) [Keitel et al., Biochem. Biophys. Res. Commun., 372:78-84 (2008). Since adipose tissue inflammations can contribute to an insulin resistant state, it is contemplated that part of the effect of GPR131 agonists to improve glucose homeostasis arises from their capacity to reduce inflammation in adipose tissue.
While certain GPR131 agonists are in early development, none are yet commercially available. Additional agonists of GPR131 for the treatment or prevention of diabetes, metabolic syndrome, liver disease, inflammation, and other diseases and conditions are therefore needed.